The role of neutrophils in ARDS is substantial. The increased accumulation of neutrophils and their activation results in enhanced chemotaxis, release of neutrophil granules and generation of abnormally high levels of oxygen metabolites. Also many inflammatory cascades are activated and many interactions between pathways. Activation of complement, especially complement fragments C3.sub.a and C5.sub.a play a role between the initiating and the actual occurrence of alveolar injury. Cytokine release form mast cells and macrophages results in the presence of tumor necrosis factor (TNF-.alpha.), elastase, endotoxin, complement C5.sub.a, IL-1, cathepsin and platelet activating factors. The presence of these compounds have an adverse effect in the use of polypeptides in the treatment of the underlying disease.
Schecter et al., Biochem Biophys Res Commun 27 (1987) p. 157 described a system of nomenclature to describe the interaction of proteases and their substrates which are widely used in protease literature. The binding site for a polypeptide substrate on a protease is seen as a series of subsites, each subsite interacts with one amino acid residue of the substrate.
Elastase as well as trypsin, chymotrypsin and kallikrein have as their active sites Asp 102, His 57, Ser 195 (chymotrypsin numbering). Elastase is a proteolytic enzyme whose action results in the splitting of a peptide chain into two or more fragments.
Elastase, Cathepsin G and azurocidin from human neutrophils are key components of body inflammatory defense. Perturbations in regulation of their activities lead to many serious pathological states. Besides pulmonary disease, elastase has been found to be involved in psoriasis, sclerosis, scleroderma, angiogenesis (e.g. proliferating hemangiomas). The presence of heparin is of particular significance in angiogenesis as well as histamine and TNF.
Many diseases require the treatment by a polypeptide such as antithrombin III, pulmonary DNase, calcitonin, insulin, and the like. Pulmonary administration of these polypeptides has been shown to be safe and effective. However, smokers inherently have excess elastase present in their lungs. However, the presence of elastase in the lungs either results in interaction with the treating polypeptide or a splitting of the peptide chain so as to cause inaction of the drug or proteolysis.
According to the present invention the sequential or co-administration of a protease inhibitor having an affinity to elastase such as alpha 1-antitrypsin or secretory leucocyte protease inhibitor with a polypeptide such as antithrombin III by a pulmonary would improve the action of the primary drug.
During surgery such as heart surgery there is reperfusion or perfusion injury. Since mast cells are present in and around the heart tissues and there is an inflammatory response, elastase is released. During the surgery it is common practice to provide an anti-clotting factor such as anti-thrombin III. Pulmonary administration has shown to be effective. However, the efficiency of anti-thrombin III is decreased because of the mediators of inflammation such as elastase and/or cathepsin G which are present in the lung.
"Sepsis syndrome" refers to the clinical condition in which patients with infection manifest sever, adverse systemic response, e.g., hypotension, or disseminated intravascular coagulation.
The risks for subsequent development of ARDS is highest in pulmonary aspiration, diffuse intravascular coagulation, severe pneumonia, hypertransfusion, long bone or pelvic fractures, bacteremia, cutaneous burns and cardiopulmonary surgery.
Early intervention of diseases or injuries before ARDS or sepsis or heart attack occurs is critical to a positive outcome and suggests that therapeutic treatment should occur prior to onset of the disease. The combination therapy can therefore reduce the damage by elastase and permit more effective use of the polypeptide used in the treatment.
U.S. Pat. No. 5,093,316 to Lezdey et al., which is incorporated herein by reference, discloses the use of alpha 1-antitrypsin in the treatment of pulmonary diseases where elastase and cathepsin G are involved.
U.S. Pat. No. 4,916,117 to Lezdey et al. discloses the use of alpha 1-antichymotrypsin in the treatment of pulmonary diseases.